Use of Ipilimumab in Metastatic CRPC That Progressed After Docetaxel Slideset on: Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-712. This activity is supported by educational grants from Bristol-Myers Squibb and Genentech.

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Background: Immunotherapy for CRPC Sipuleucel-T: autologous dendritic cell–based vaccine[1] Approved for asymptomatic or minimally symptomatic mCRPC[1] IMPACT trial: extension of median OS by 4.1 mos vs placebo[2] No effect on PSA concentration, tumor regression, or PFS Ipilimumab: fully human monoclonal antibody against CTLA-4[3] Promotes local tumor infiltration by CD8+ T cells[4] May sensitize tumor cells to antigen-specific cytotoxic T-cells[5] Local RT combined with anti–CTLA-4 antibody can induce abscopal effect mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; RT, radiation therapy. 1. Sipuleucel-T [package insert]. 2. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 3. Fong L, et al. J Clin Oncol. 2008;26:5275-5283. 4. Kaur P, et al. Front Oncol. 2012;2:191. 5. Harris TJ, et al. Prostate. 2008;68:1319-1329.

Men with mCRPC who progressed after docetaxel CA184-043: Ipilimumab vs Placebo After RT in Docetaxel-Refractory mCRPC Stratification: ECOG PS 0 vs 1; alk phos < 1.5 vs ≥ 1.5 x ULN; hemoglobin < 110 vs ≥ 110 g/L; investigator site Maintenance ipilimumab or placebo continued every 3 mos until progression, unacceptable toxicity, or death Radiotherapy* followed by Placebo IV every 3 wks up to 4 doses (n = 400) Men with mCRPC who progressed after docetaxel (N = 799) Radiotherapy* followed by Ipilimumab 10 mg/kg IV every 3 wks up to 4 doses (n = 399) Alk phos, alkaline phosphatase; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PS, performance status; ULN, upper limit of normal. *Single dose of 8 Gy for ≥ 5 bone fields at investigator’s discretion Primary endpoint: median OS Secondary endpoints: PFS, pain response, and safety Kwon ED, et al. Lancet Oncol. 2014;15:700-712.

CA184-043: Overall and Progression-Free Survival 100 Ipilimumab Censored Placebo Censored HR: 0-85 (95% CI: 0.72-1.00; P = .053) Exploratory Piecewise OS Time Range HR 95% CI Up to 5 mos 1.46 1.10-1.95 5-12 mos 0.65 0.50-0.85 Beyond 12 mos 0.60 0.43-0.86 90 80 70 60 XXXXXXXX OS (%) 50 40 30 20 10 OS, overall survival; PFS, progression-free survival. 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Mos Ipilimumab significantly improved median PFS 4.0 mos (95% CI: 3.6-4.3) with ipilimumab vs 3.1 mos (95% CI: 2.9-3.4) with placebo (HR: 0.7; 95% CI: 0.61-0.82; P < .0001) Kwon ED, et al. Lancet Oncol. 2014;15:700-712.

CA184-043: OS Subset Analyses Prespecified subset analyses suggest stronger ipilimumab benefit for certain patient subgroups Presence of visceral metastases only prognostic feature with significant interaction with treatment HR: 1.644 (95% CI: 1.157- 2.336; P = .0056) n/N (Ipilimumab vs Placebo) HR (95% CI) Age Younger than 70 yrs 70 yrs or older ECOG performance status 0 1 Alkaline phosphatase < 1.5 x ULN ≥ 1.5 x ULN Hemoglobin concentration < 110 g/L ≥ 110 g/L Number of bone regions with metastases 1 ≥ 2 Presence of visceral metastases Yes No 138/215 vs 172/234 131/184 vs 133/166 98/167 vs 123/168 171/232 vs 182/232 142/243 vs 166/243 127/156 vs 139/157 98/111 vs 103/113 171/288 vs 202/287 184/290 vs 207/276 72/89 vs 76/88 94/113 vs 93/114 173/280 vs 206/275 0.81 (0.64-1.01) 0.88 (0.69-1.13) 0.72 (0.55-0.94) 0.94 (0.76-1.16) 0.78 (0.62-0.97) 0.95 (0.75-1.21) 0.98 (0.74-1.29) 0.79 (0.64-0.97) 0.78 (0.64-0.96) 0.93 (0.68-1.29) 1.20 (0.90-1.60) 0.73 (0.59-0.89) ECOG, Eastern Cooperative Oncology Group; OS, overall survival; ULN, upper limit of normal. 0.5 1.0 1.5 Kwon ED, et al. Lancet Oncol. 2014;15:700-712. Favors ipilimumab Favors placebo

CA184-043: Post hoc Subset Analysis of OS Data OS in Favorable Prognosis Subset* OS in Poor Prognosis Subset† Ipilimumab Censored Placebo Censored HR: 0.62 (95% CI: 0.45- 0.86; P = .0038) 100 100 90 90 HR: 0.98 (95% CI: 0.81-1.19; P = .8756) 80 80 70 70 60 60 OS (%) 50 OS (%) 50 40 40 Alk phos, alkaline phosphatase; Hb, hemoglobin; OS, overall survival; ULN, upper limit of normal. 30 30 20 20 10 *Alk phos < 1.5 X ULN, Hb > 110 g/L, and no visceral metastases 10 † Alk phos ≥ 1.5 X ULN or Hb < 110 g/L or visceral metastases 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Mos Mos Kwon ED, et al. Lancet Oncol. 2014;15:700-712.

CA184-043: Adverse Events: Grade 3/4 Most common immune-related AEs of any grade (≥ 5% pts) among pts on ipilimumab arm: diarrhea, pruritus, rash, colitis, elevated ALT or AST 5 pts in the ipilimumab arm experienced gastrointestinal perforation AE Ipilimumab (n = 393) Placebo (n = 396) Any grade 3/4 AE, % 59 41 Grade 3/4 AE in > 5% of pts, %   Diarrhea 16 2 Fatigue 11 9 Anemia 10 Asthenia 6 3 On-study deaths due to AE, % 1 Treatment discontinuation due to AE, % 35 Grade 3/4 immune-related AE, % 26 Deaths attributed to study drug toxicity, n 4 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Kwon ED, et al. Lancet Oncol. 2014;15:700-712.

Strengths and Weaknesses Well-designed trial with well-defined endpoint (OS) Treatment arms balanced and representative of common patient population (few exclusion criteria; allowed enrollment of men with visceral metastases) Suggestion of efficacy in smaller volume disease corroborated by findings in metastatic melanoma Weaknesses Not all subgroup analyses prespecified Suggestion of improved efficacy in less extensive disease hypothesis-generating only Rationale for 10 mg/kg ipilimumab dose not specified in paper (3 mg/kg used for melanoma) Trial did not address role of radiation and potential synergies with ipilimumab OS, overall survival. 1. Kwon ED, et al. Lancet Oncol. 2014;15:700-712. 2. ClinicalTrials.gov. NCT01057810.

Conclusions Study failed to meet primary endpoint of OS[1] Ipilimumab did not statistically significantly improve median OS vs placebo in patients with mCRPC who had progressed after docetaxel (P = .053) Exploratory piecewise hazard model suggested improved survival associated with ipilimumab at later time points (> 5 mos) Prespecified and post hoc subset analyses suggest ipilimumab benefit primarily in patients with favorable prognostic profile[1] Absence of visceral metastases Alkaline phosphatase < 1.5 x ULN Hemoglobin ≥ 110 g/L Ongoing phase III trial (CA184-095) in chemotherapy-naive patients with mCRPC and no visceral metastases[2] mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; ULN, upper limit of normal. 1. Kwon ED, et al. Lancet Oncol. 2014;15:700-712. 2. ClinicalTrials.gov. NCT01057810.

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